Molecular Imaging of Lower Extremity Peripheral Arterial Disease: An Emerging Field in Nuclear Medicine

Mitchel R Stacy, Mitchel R Stacy

Abstract

Peripheral arterial disease (PAD) is an atherosclerotic disorder of non-coronary arteries that is associated with vascular stenosis and/or occlusion. PAD affecting the lower extremities is characterized by a variety of health-related consequences, including lifestyle-limiting intermittent claudication, ulceration of the limbs and/or feet, increased risk for lower extremity amputation, and increased mortality. The diagnosis of lower extremity PAD is typically established by using non-invasive tests such as the ankle-brachial index, toe-brachial index, duplex ultrasound, and/or angiography imaging studies. While these common diagnostic tools provide hemodynamic and anatomical vascular assessments, the potential for non-invasive physiological assessment of the lower extremities has more recently emerged through the use of magnetic resonance- and nuclear medicine-based approaches, which can provide insight into the functional consequences of PAD-related limb ischemia. This perspectives article specifically highlights and discusses the emerging applications of clinical nuclear medicine techniques for molecular imaging investigations in the setting of lower extremity PAD.

Keywords: computed tomography; molecular imaging; peripheral arterial disease (PAD); positron emission tomography (PET); single photon emission computed tomography (SPECT).

Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Stacy.

Figures

Figure 1
Figure 1
SPECT/CT imaging of the perfusion response to lower extremity revascularization in patients with CLTI. Non-invasive imaging identified differential perfusion responses to peripheral balloon angioplasty in (A) a patient with a low perfusion response who underwent amputation within one month, and (B) a patient who had a high relative perfusion response and remained amputation-free for one year after intervention. Adapted from Chou et al. (22). For a complete description of perfusion imaging methodology, please refer to Chou et al. (22).
Figure 2
Figure 2
18F-NaF PET/CT imaging of active microcalcification in PAD. (A) Axial, (B) coronal, and (C) sagittal fused 18F-NaF PET/CT images acquired in a 63-year old female patient with CLTI and type 2 diabetes mellitus demonstrates the active process of microcalcification in above- and below-the-knee arteries. Non-contrast CT images were acquired for attenuation correction of PET data, followed by static PET imaging of the lower extremities 75 min after intravenous administration of 18F-NaF (296 MBq). SUV, standardized uptake value.

References

    1. McDermott MM, Ferrucci L, Gonzalez-Freire M, Kosmac K, Leeuwenburgh C, Peterson CA, et al. . Skeletal muscle pathology in peripheral artery disease: a brief report. Arter Thromb Vasc Biol. (2020) 40:2577–85. 10.1161/ATVBAHA.120.313831
    1. Criqui MH, Matsushita K, Aboyans V, Hess CN, Hicks CW, Kwan TW, et al. . Lower extremity peripheral artery disease: contemporary epidemiology, management gaps, and future directions: a scientific statement from the American Heart Association. Circulation. (2021) 144:e171–91. 10.1161/CIR.0000000000001005
    1. Misra S, Shishehbor MH, Takahashi EA, Aronow HD, Brewster LP, Bunte MC, et al. . Perfusion assessment in critical limb ischemia: principles for understanding and the development of evidence and evaluation of devices: a scientific statement from the American Heart Association. Circulation. (2019) 140:e657–72. 10.1161/CIR.0000000000000708
    1. Shu J, Santulli G. Update on peripheral artery disease: Epidemiology and evidence-based facts. Atherosclerosis. (2018) 275:379–81. 10.1016/j.atherosclerosis.2018.05.033
    1. Andras A, Ferket B. Screening for peripheral arterial disease. Cochrane Database Syst Rev. (2014) 7:CD010835. 10.1002/14651858.CD010835.pub2
    1. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. . 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. (2017) 69:e71–e126. 10.1016/j.jacc.2016.11.007
    1. Smith BC, Quimby EH. The use of radioactive sodium as a tracer in the study of peripheral vascular disease. Radiology. (1945) 45:335–46. 10.1148/45.4.335
    1. Kety S. Measurement of regional circulation by the local clearance of radioactive sodium. Am Hear J. (1949) 38:321–8. 10.1016/0002-8703(49)90845-5
    1. Seder JS, Botvinick EH, Rahimtoola SH, Goldstone J, Price DC. Detecting and localizing peripheral arterial disease: assessment of 201Tl scintigraphy. AJR Am J Roentgenol. (1981) 137:373–80. 10.2214/ajr.137.2.373
    1. Hamanaka D, Odori T, Maeda H, Ishii Y, Hayakawa K, Torizuka K, et al. . Quantitative assessment of scintigraphy of the legs using 201Tl. Eur J Nucl Med. (1984) 9:12–6. 10.1007/BF00254343
    1. Galanakis N, Maris TG, Kontopodis N, Ioannou CV, Tsetis K, Karantanas A, et al. . The role of dynamic contrast-enhanced MRI in evaluation of percutaneous transluminal angioplasty outcome in patients with critical limb ischemia. Eur J Radiol. (2020) 129:109081. 10.1016/j.ejrad.2020.109081
    1. Zheng J, Sorensen C, Li R, An H, Hildebolt CF, Zayed MA, et al. . Deteriorated regional calf microcirculation measured by contrast-free MRI in patients with diabetes mellitus and relation with physical activity. Diab Vasc Dis Res. (2021) 18:1–8. 10.1177/14791641211029002
    1. Stacy MR, Qiu M, Papademetris X, Caracciolo CM, Constable RT, Sinusas AJ. Application of BOLD MR imaging for evaluating regional volumetric foot tissue oxygenation: a feasibility study in healthy volunteers. Eur J Vasc Endovasc Surg. (2016) 51:743–9. 10.1016/j.ejvs.2016.02.008
    1. Stacy MR, Caracciolo CM, Qiu M, Pal P, Varga T, Constable RT, et al. . Comparison of regional skeletal muscle tissue oxygenation in college athletes and sedentary control subjects using quantitative BOLD MR imaging. Physiol Rep. (2016) 4:e12903. 10.14814/phy2.12903
    1. Suo S, Zhang L, Tang H, Ni Q, Li S, Mao H, et al. . Evaluation of skeletal muscle microvascular perfusion of lower extremities by cardiovascular magnetic resonance arterial spin labeling, blood oxygenation level-dependent, and intravoxel incoherent motion techniques. J Cardiovasc Magn Reson. (2018) 20:18. 10.1186/s12968-018-0441-3
    1. Davidson BP, Hodovan J, Mason OR, Moccetti F, Gupta A, Muller M, et al. . Limb perfusion during exercise assessed by contrast ultrasound varies according to symptom severity in patients with peripheral artery disease. J Am Soc Echocardiogr. (2019) 32:1086–94. 10.1016/j.echo.2019.05.001
    1. Mason OR, Davidson BP, Sheeran P, Muller M, Hodovan JM, Sutton J, et al. . Augmentation of tissue perfusion in patients with peripheral artery disease using microbubble cavitation. JACC Cardiovasc Imaging. (2020) 13:641–51. 10.1016/j.jcmg.2019.06.012
    1. Younes A, Songadele JA, Maublant J, Platts E, Pickett R, Veyre A. Mechanism of uptake of technetium-tetrofosmin. II: Uptake into isolated adult rat heart mitochondria. J Nucl Cardiol. (1995) 2:327–33. 10.1016/S1071-3581(05)80077-7
    1. Alvelo JL, Papademetris X, Mena-Hurtado C, Jeon S, Sumpio BE, Sinusas AJ, et al. . Radiotracer imaging allows for noninvasive detection and quantification of abnormalities in angiosome foot perfusion in diabetic patients with critical limb ischemia and nonhealing wounds. Circ Cardiovasc Imaging. (2018) 11:e006932. 10.1161/CIRCIMAGING.117.006932
    1. Chou TH, Tram NK, Eisert SN, Bobbey AJ, Atway SA, Go MR, et al. . Dual assessment of abnormal microvascular foot perfusion and lower extremity calcium burden in a patient with critical limb ischemia using hybrid SPECT/CT imaging. Vasc Med. (2021) 26:225–7. 10.1177/1358863X20964563
    1. Chou TH, Atway SA, Bobbey AJ, Sarac TP, Go MR, Stacy MR. SPECT/CT imaging: a non-invasive approach for evaluating serial changes in angiosome foot perfusion in critical limb ischemia. Adv Wound Care. (2020) 9:103–10. 10.1089/wound.2018.0924
    1. Chou TH, Alvelo JL, Janse S, Papademetris X, Sumpio BE, Mena-Hurtado C, et al. . Prognostic value of radiotracer-based perfusion imaging in critical limb ischemia patients undergoing lower extremity revascularization. JACC Cardiovasc Imaging. (2021) 14:1614–24. 10.1016/j.jcmg.2020.09.033
    1. Takagi G, Miyamoto M, Fukushima Y, Yasutake M, Tara S, Takagi I, et al. . Imaging angiogenesis using 99mTc-MAA scintigraphy in patients with peripheral artery disease. J Nucl Med. (2016) 57:192–7. 10.2967/jnumed.115.160937
    1. Hashimoto H, Fukushima Y, Kumita S-I, Miyamoto M, Takagi G, Yamazaki J, et al. . Prognostic value of lower limb perfusion single-photon emission computed tomography-computed tomography in patients with lower limb atherosclerotic peripheral artery disease. Jpn J Radiol. (2017) 35:68–77. 10.1007/s11604-016-0602-y
    1. Chou TH, Janse S, Sinusas AJ, Stacy MR. SPECT/CT imaging of lower extremity perfusion reserve: a non-invasive correlate to exercise tolerance and cardiovascular fitness in patients undergoing clinically indicated myocardial perfusion imaging. J Nucl Cardiol. (2020) 27:1923–33. 10.1007/s12350-019-02019-w
    1. Treat-Jacobson D, McDermott MM, Bronas UG, Campia U, Collins TC, Criqui MH, et al. . Optimal exercise programs for patients with peripheral artery disease: a scientific statement from the American Heart Association. Circulation. (2019) 139:e10–33. 10.1161/CIR.0000000000000623
    1. Burchert W, Schellong S, van den Hoff J, Meyer G-J, Alexander K, Hundeshagen H. Oxygen-15-water PET assessment of muscular blood flow in peripheral vascular disease. J Nucl Med. (1997) 38:93–8.
    1. Schmidt MA, Chakrabarti A, Shamim-Uzzaman Q, Kaciroti N, Koeppe RA, Rajagopalan S. Calf flow reserve with H(2)(15)O PET as a quantifiable index of lower extremity flow. J Nucl Med. (2003) 44:915−9.
    1. Scremin OU, Figoni SF, Norman K, Scremin AME, Kunkel CF, Opava-Rutter D, et al. . Preamputation evaluation of lower-limb skeletal muscle perfusion with (15)O H2O positron emission tomography. Am J Phys Med Rehabil. (2010) 89:473–86. 10.1097/PHM.0b013e3181d89b08
    1. Iida H, Kanno I, Takahashi A, Miura S, Murakami M, Takahashi K, et al. . Measurement of absolute myocardial blood flow with H215O and dynamic positron-emission tomography. Strategy for quantification in relation to the partial-volume effect. Circulation. (1988) 78:104–15. 10.1161/01.CIR.78.1.104
    1. Stacy MR. Radionuclide imaging of atherothrombotic diseases. Curr Cardiovasc Imaging Rep. (2019) 12:17. 10.1007/s12410-019-9491-7
    1. Cocker MS, Spence JD, Hammond R, deKemp RA, Lum C, Wells G, et al. . [18F]-fluorodeoxyglucose PET/CT imaging as a marker of carotid plaque inflammation: comparison to immunohistology and relationship to acuity of events. Int J Cardiol. (2018) 271:378–86. 10.1016/j.ijcard.2018.05.057
    1. Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC, et al. . In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol. (2006) 48:1818–24. 10.1016/j.jacc.2006.05.076
    1. Zhang Z, Machac J, Helft G, Worthley SG, Tang C, Zaman AG, et al. . Non-invasive imaging of atherosclerotic plaque macrophage in a rabbit model with F-18 FDG PET: a histological correlation. BMC Nucl Med. (2006) 6:3. 10.1186/1471-2385-6-3
    1. De Boer SA, Hovinga-De Boer MC, Heerspink HJL, Lefrandt JD, van Roon AM, Lutgers HL, et al. . Arterial stiffness is positively associated with 18F-fluorodeoxyglucose positron emission tomography-assessed subclinical vascular inflammation in people with early type 2 diabetes. Diabetes Care. (2016) 39:1440–7. 10.2337/dc16-0327
    1. Ishii H, Nishio M, Takahashi H, Aoyama T, Tanaka M, Toriyama T, et al. . Comparison of atorvastatin 5 and 20 mg/d for reducing F-18 fluorodeoxyglucose uptake in atherosclerotic plaques on positron emission tomography/computed tomography: a randomized, investigator-blinded, open-label, 6-month study in Japanese adults scheduled. Clin Ther. (2010) 32:2337–47. 10.1016/j.clinthera.2010.12.001
    1. Jiang Y, Fan J, Li Y, Wu G, Wang Y, Yang J, et al. . Rapid reduction in plaque inflammation by sonodynamic therapy in patients with symptomatic femoropopliteal peripheral artery disease: a randomized controlled trial. Int J Cardiol. (2021) 325:132–9. 10.1016/j.ijcard.2020.09.035
    1. Dregely I, Koppara T, Nekolla SG, Nahrig J, Kuhs K, Langwieser N, et al. . Observations with simultaneous 18F-FDG PET and MR imaging in peripheral artery disease. JACC Cardiovasc Imaging. (2017) 10:709–11. 10.1016/j.jcmg.2016.06.005
    1. Czernin J, Satyamurthy N, Schiepers C. Molecular mechanisms of bone 18F-NaF deposition. J Nucl Med. (2010) 51:1826–9. 10.2967/jnumed.110.077933
    1. Derlin T, Richter U, Bannas P, Begemann P, Buchert R, Mester J, et al. . Feasibility of (18)F-sodium fluoride PET/CT for imaging of atherosclerosis plaque. J Nucl Med. (2010) 51:862–5. 10.2967/jnumed.110.076471
    1. Janssen T, Bannas P, Herrmann J, Veldhoen S, Busch JD, Treszl A, et al. . Association of linear (18)F-sodium fluoride accumulation in femoral arteries as a measure of diffuse calcification with cardiovascular risk factors: a PET/CT study. J Nucl Cardiol. (2013) 20:569–77. 10.1007/s12350-013-9680-8
    1. Asadollahi S, Rojulpote C, Bhattaru A, Patil S, Gonuguntla K, Karambelkar P, et al. . Comparison of atherosclerotic burden in non-lower extremity arteries in patients with and without peripheral artery disease using 18F-NaF-PET/CT imaging. Am J Nucl Med Mol Imaging. (2020) 10:272–8.
    1. Takx RAP, van Asperen R, Bartstra JW, Zwakenberg SR, Wolterink JM, Celeng C, et al. . Determinants of 18F-NaF uptake in femoral arteries in patients with type 2 diabetes mellitus. J Nucl Cardiol. (2020) 28:2700–5. 10.1007/s12350-020-02099-z
    1. Eisert SN, Chou TH, Bobbey AJ, Go MR, Stacy MR. Noninvasive detection of active microcalcification in an occlusive peripheral vascular aneurysm using 18F-NaF PET/CT imaging. Clin Nucl Med. (2020) 45:1029–31. 10.1097/RLU.0000000000003344
    1. Chowdhury MM, Tarkin JM, Albaghdadi MS, Evans NR, Le EPV, Berrett TB, et al. . Vascular positron emission tomography and restenosis in symptomatic peripheral arterial disease: a prospective clinical study. JACC Cardiovasc Imaging. (2020) 13:1008–17. 10.1016/j.jcmg.2019.03.031
    1. Reijrink M, de Boer SA, Te Velde-Keyzer CA, Sluiter JKE, Pol RA, Heerspink HJL, et al. . [18F]FDG and [18F]NaF as PET markers of systemic atherosclerosis progression: a longitudinal descriptive imaging study in patients with type 2 diabetes mellitus. J Nucl Cardiol. (2021). 10.1007/s12350-021-02781-w. [Epub ahead of print].
    1. Chou TH, Stacy MR. Clinical applications for radiotracer imaging of lower extremity peripheral arterial disease and critical limb ischemia. Mol Imaging Biol. (2020) 22:245–55. 10.1007/s11307-019-01425-3
    1. Fernandez-Friera L, Fuster V, Lopez-Melgar B, Oliva B, Sanchez-Gonzalez J, Macias A, et al. . Vascular inflammation in subclinical atherosclerosis detected by hybrid PET/MRI. J Am Coll Cardiol. (2019) 73:1371–82. 10.1016/j.jacc.2018.12.075
    1. Lohrke J, Siebeneicher H, Berger M, Reinhardt M, Berndt M, Mueller A, et al. . 18F-GP1, a novel PET tracer designed for high-sensitivity, low-background detection of thrombi. J Nucl Med. (2017) 58:1094–9. 10.2967/jnumed.116.188896
    1. Chae SY, Kwon T-W, Jin S, Kwon SU, Sung C, Oh SJ, et al. . A phase 1, first-in-human study of 18F-GP1 positron emission tomography for imaging acute arterial thrombosis. EJNMMI Res. (2019) 9:3. 10.1186/s13550-018-0471-8
    1. Lee N, Oh I, Chae SY, Jin S, Oh SJ, Lee SJ, et al. . Radiation dosimetry of [18F]GP1 for imaging activated glycoprotein IIb/IIIa receptors with positron emission tomography in patients with acute thromboembolism. Nucl Med Biol. (2019) 72–73:45–48. 10.1016/j.nucmedbio.2019.07.003
    1. Andrews JPM, Portal C, Walton T, Macaskill MG, Hadoke PWF, Corral CA, et al. . Non-invasive in vivo imaging of acute thrombosis: development of a novel factor XIIIa radiotracer. Eur Hear J Cardiovasc Imaging. (2020) 21:673–82. 10.1093/ehjci/jez207
    1. Hugenberg V, Zerna M, Berndt M, Zabel R, Preuss R, Rolfsmeier D, et al. . GMP-compliant radiosynthesis of [18F]GP1, a novel PET tracer for the detection of thrombi. Pharm. (2021) 14:739. 10.3390/ph14080739
    1. Stacy MR, Yu DY, Maxfield MW, Jaba IM, Jozwik BP, Zhuang ZW, et al. . Multimodality imaging approach for serial assessment of regional changes in lower extremity arteriogenesis and tissue perfusion in a porcine model of peripheral arterial disease. Circ Cardiovasc Imaging. (2014) 7:92–9. 10.1161/CIRCIMAGING.113.000884
    1. Stacy MR, Sinusas AJ. Novel applications of radionuclide imaging in peripheral vascular disease. Cardiol Clin. (2016) 34:167–77. 10.1016/j.ccl.2015.06.005
    1. Johnson LL, Johnson J, Ali Z, Tekabe Y, Ober R, Geist G, et al. . VEFG receptor targeted imaging of angiogenic response to limb ischemia in diabetic vs. non-diabetic Yucatan minipigs. EJNMMI Res. (2020) 10:48. 10.1186/s13550-020-00626-0
    1. Goggi JL, Haslop A, Boominathan R, Chan K, Soh V, Cheng P, et al. . Imaging the proangiogenic effects of cardiovascular drugs in a diabetic model of limb ischemia. Contrast Media Mol Imaging. (2019) 2019:2538909. 10.1155/2019/2538909

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir